Publication:
Pharmacological Chaperoning in Fabry Disease

Simple item page
dc.contributor.advisorScott C Garman
dc.contributor.authorRogich, Jerome
dc.contributor.departmentUniversity of Massachusetts Amherst
dc.contributor.departmentBiochemistry
dc.date2023-09-23T04:33:36.000
dc.date.accessioned2024-04-26T21:14:55Z
dc.date.available2011-08-12T00:00:00Z
dc.date.issued2011-01-01
dc.date.submittedSeptember
dc.description.abstractFabry Disease is an X-‐linked lysosomal storage disorder characterized by a variety of symptoms including hypohydrosis, seizures, cardiac abnormalities, skin lesions, and chronic pain. These symptoms stem from a lack of functional endogenous α-‐ Galactosidase A (α-GAL), which leads to an accrual of its natural substrate. The severity of the disease symptoms can be directly correlated with the amount of residual enzyme activity. It has been shown that an imino sugar, 1-deoxygalactonojirimycin (DGJ), can increase enzymatic activity and clear excess substrate. This pH-‐dependent chaperoning phenomenon is believed to arise from the presence of aspartic acid 170 in the active site. This key residue may become protonated at lower pH, preventing a buried salt bridge from being formed. We mutated this residue to an alanine, abolishing activity, and making traditional assays impractical. We have measured the KD of chaperone for this modified active site through crystallography. Previous crystallographic studies on this enzyme have also shown a preliminary second binding site on the surface of α-Galactosidase that prefers the β-Galactose anomer. When β-Galactose binds it buries a greater surface area than when α‐Galactose binds to the active site. Binding of this site by a small molecule should stabilize the native state of the enzyme, but would be sterically occluded from inhibiting active site. We have probed this second site by soaking crystals of α‐Galactosidase with a small library of compounds.
dc.description.degreeMaster of Science (M.S.)
dc.identifier.doihttps://doi.org/10.7275/2151998
dc.identifier.urihttps://hdl.handle.net/20.500.14394/47626
dc.relation.urlhttps://scholarworks.umass.edu/cgi/viewcontent.cgi?article=1786&context=theses&unstamped=1
dc.source.statuspublished
dc.subjectPharmacological Chaperone Fabry Disease X-ray Crystallography
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectBiochemistry
dc.subjectBiophysics
dc.subjectEnzymes and Coenzymes
dc.subjectMedicinal-Pharmaceutical Chemistry
dc.subjectMolecular Biology
dc.subjectOther Biochemistry, Biophysics, and Structural Biology
dc.subjectOther Chemicals and Drugs
dc.subjectPharmaceutical Preparations
dc.subjectStructural Biology
dc.titlePharmacological Chaperoning in Fabry Disease
dc.typeopen
dc.typearticle
dc.typethesis
digcom.contributor.authorisAuthorOfPublication|email:jrogich@gmail.com|institution:University of Massachusetts Amherst|Rogich, Jerome
digcom.date.embargo2011-08-12T00:00:00-07:00
digcom.identifiertheses/712
digcom.identifier.contextkey2151998
digcom.identifier.submissionpaththeses/712
dspace.entity.typePublication
Files
Original bundle
Now showing 1 - 2 of 2
No Thumbnail Available
Name:
Jerome_Rogich_Thesis_Grad_School_Revisions.docx
Size:
44.6 MB
Format:
Microsoft Word XML
Name: Jerome_Rogich_Thesis_Grad_School_Revisions.docx
Size: 44.6 MB
Kind: Microsoft Word XML
No Thumbnail Available
Name:
Jerome_Rogich_Thesis_Grad_School_Revisions_2_BINDER.pdf
Size:
66.24 MB
Format:
Adobe Portable Document Format
Name: Jerome_Rogich_Thesis_Grad_School_Revisions_2_BINDER.pdf
Size: 66.24 MB
Kind: Adobe PDF
Collections
Masters Theses